Combinatorial clinical trials of PARP inhibitors with immunotherapies are ongoing, yet the immunomodulatory effects of PARP inhibition have been incompletely studied. Here, we sought to dissect the mechanisms underlying PARP inhibitor-induced changes in the tumor microenvironment of BRCA1-defi cient triple-negative breast cancer (TNBC). We demonstrate that the PARP inhibitor olaparib induces CD8 + T-cell infi ltration and activation in vivo , and that CD8 + T-cell depletion severely compromises antitumor effi cacy. Olaparib-induced T-cell recruitment is mediated through activation of the cGAS/STING pathway in tumor cells with paracrine activation of dendritic cells and is more pronounced in HR-defi cient compared with HR-profi cient TNBC cells and in vivo models. CRISPR-mediated knockout of STING in cancer cells prevents proinfl ammatory signaling and is suffi cient to abolish olaparib-induced T-cell infi ltration in vivo. These fi ndings elucidate an additional mechanism of action of PARP inhibitors and provide a rationale for combining PARP inhibition with immunotherapies for the treatment of TNBC. SIGNIFICANCE: This work demonstrates cross-talk between PARP inhibition and the tumor microenvironment related to STING/TBK1/IRF3 pathway activation in cancer cells that governs CD8 + T-cell recruitment and antitumor effi cacy. The data provide insight into the mechanism of action of PARP inhibitors in BRCA-associated breast cancer.

The objective of this review was to clarify what health literacy represents. A systematic review with qualitative syntheses was performed (CRD42017065149). Studies concerning health literacy in all settings were included. Studies before 15 March 2017 were identified from PubMed, Medline, Embase, Web of Science, Scopus, PsycARTICLES and the Cochrane Library. The included literature either had defined the concept of health literacy or made a detailed explanation of health literacy. A total of 34 original studies met the inclusion criteria, including 13 involved in previous systematic reviews and 21 new studies. Health literacy was commonly conceptualised as a set of knowledge, a set of skills or a hierarchy of functions (functional-interactive-critical). The construct of health literacy covers three broad elements: (1) knowledge of health, healthcare and health systems; (2) processing and using information in various formats in relation to health and healthcare; and (3) ability to maintain health through self-management and working in partnerships with health providers. Health literacy is defined as the ability of an individual to obtain and translate knowledge and information in order to maintain and improve health in a way that is appropriate to the individual and system contexts. This definition highlights the diversity of needs from different individuals and the importance of interactions between individual consumers, healthcare providers and healthcare systems.

Conventional approaches to identify secreted factors that regulate homeostasis are limited in their abilities to identify the tissues/cells of origin and destination. We established a platform to identify secreted protein trafficking between organs using an engineered biotin ligase (BirA*G3) that biotinylates, promiscuously, proteins in a subcellular compartment of one tissue. Subsequently, biotinylated proteins are affinity-enriched and identified from distal organs using quantitative mass spectrometry. Applying this approach in Drosophila, we identify 51 muscle-secreted proteins from heads and 269 fat body-secreted proteins from legs/muscles, including CG2145 (human ortholog ENDOU) that binds directly to muscles and promotes activity. In addition, in mice, we identify 291 serum proteins secreted from conditional BirA*G3 embryo stem cell-derived teratomas, including low-abundance proteins with hormonal properties. Our findings indicate that the communication network of secreted proteins is vast. This approach has broad potential across different model systems to identify cell-specific secretomes and mediators of interorgan communication in health or disease.